PROJECT SUMMARY Over 20.3 million adults in the U.S. are estimated to have a substance use disorder (SUD); and, an estimated 2 million Americans have had an opioid use disorder (OUD) involving prescription opioids and about 600,000 have had an OUD involving heroin. The number of overdose deaths from illicit opioids including heroin and synthetic opioids has tripled from 2011 to 2015 in the U.S. Among the more than half-million adults entering addiction treatment for prescription opioid abuse every year, 50%-60% report co-morbid chronic pain and 80% report that pain triggers relapse. High rates of relapse are not surprising because substance misuse may cause adverse structural and functional brain changes in the same brain regions that need to be engaged to initiate recovery and maintain abstinence. Exercise has been shown to reduce substance cravings and reduce depression and anxiety and may help reduce weight gain induced by methadone and anti-psychotic drug treatments; and, exercise, particularly at higher intensities, may produce an analgesic effect improving pain measures in chronic pain patients. Exercise may act by increasing growth and brain-derived neurotrophic factors that stimulate endogenous dopaminergic, opioidergic and serotoninergic systems that, in turn, enhance plasticity, learning and memory. These effects may help repair the structural and functional brain changes caused by substance abuse and chronic pain and help ?offset? reward seeking and craving of substances while improving physical and mental health. However, most residential drug treatment programs do not currently offer a structured exercise program. We have developed an ?assisted? exercise technology that enables active patient engagement and mechanical assistance to help patients pedal faster than their voluntary rates. We have previously shown that ?assisted? exercise on a stationary cycle provides global improvements in motor function and increased activity in cortical and subcortical brain regions consistent with neural activation patterns after applying a dopamine agonist in Parkinson?s disease patients, suggesting that ?assisted? exercise may be modulating dopamine levels in the brain. In addition, we have shown that ?assisted? cycling improves motor function and recovery in stroke patients. We have also developed a novel self-regulation/cognitive behavioral therapy (CBT) program that co-addresses opioid addiction and pain (STOP), which has shown efficacy on pain tolerance, cravings and functional engagement in daily activities in outpatients. In response to RFA-AT-19-006, we propose to take a multi-phase optimization strategy (MOST) approach to refining our intervention protocols and testing feasibility with our community partners (R61 Phase) and evaluating the effects of exercise and I-STOP (STOP modified for inpatients) as adjunctive treatments to Medication Assisted Treatment (MAT) in adults with an OUD and chronic pain enrolled in residential treatment programs to decrease drug cravings and pain and increase adherence to MAT (methadone, buprenorphine) (R33 Phase).